Chiral Binaphthol-Catalyzed Enantioselective Conjugate Addition of Alkenyl and Arylboronic Acids to α,ß-Unsaturated Cyclic N-Sulfonyl Ketimines.

The chiral binaphthol-catalyzed enantioselective conjugate addition of alkenylboronic acids and heteroarylboronic acids to cyclic N-sulfonyl ketimines is reported, providing the 1,4-addition products in high yields and moderate to excellent enantioselectivities (up to >99% ee). This mild, scalable catalytic system exhibits high efficiency and broad substrate scopes. Additionally, arylboronic acids were viable nucleophiles under more forcing conditions.

Efficacy and Safety of Different Preemptive Analgesia Measures in Pain Management after Laparoscopic Cholecystectomy: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The purpose of this systematic review and network meta-analysis was to evaluate the efficacy and safety of different preemptive analgesia measures given before laparoscopic cholecystectomy (LC) for postoperative pain in patients. METHODS: We conducted a comprehensive search in databases including PubMed, Web of Science, Embase, and the Cochrane Library up to March 2024, and collected relevant research data on the 26 preemptive analgesia measures defined in this article in LC surgery. Outcomes included postoperative Visual Analogue Scores (VAS) at different times (2, 6, 12, and 24 h), opioid consumption within 24 h post-operation, time to first rescue analgesia, incidence of postoperative nausea and vomiting (PONV), and incidence of postoperative headache or dizziness. RESULTS: Forty-nine articles involving 5987 patients were included. The network meta-analysis revealed that multimodal analgesia, nerve blocks, pregabalin, and gabapentin significantly reduced postoperative pain scores at all postoperative time points and postoperative opioid consumption compared to placebo. Tramadol, pregabalin, and gabapentin significantly extended the time to first rescue analgesia. Ibuprofen was the best intervention for reducing PONV incidence. Tramadol significantly reduced the incidence of postoperative headache or dizziness. Subgroup analysis of different doses of pregabalin and gabapentin showed that compared to placebo, pregabalin (300 mg, 150 mg) and gabapentin (600 mg, 300 mg, and 20 mg/kg) were all more effective without significant differences in efficacy between these doses. Higher doses increased the incidence of PONV and postoperative headache and dizziness, with gabapentin 300 mg having a lower adverse drug reaction (ADR) incidence. CONCLUSIONS: Preemptive analgesia significantly reduced postoperative pain intensity, opioid consumption, extended the time to first rescue analgesia, and decreased the incidence of PONV and postoperative headache and dizziness. Multimodal analgesia, nerve blocks, pregabalin, and gabapentin all showed good efficacy. Gabapentin 300 mg given preoperatively significantly reduced postoperative pain and ADR incidence, recommended for preemptive analgesia in LC. TRIAL REGISTRATION: PROSPERO CRD42024522185.

Chiral-Boron Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of 2'-Hydroxychalcones with N-2,2,2-Trifluoroethylisatin Ketimines.

A highly efficient asymmetric [3 + 2] cycloaddition reaction of 2'-hydroxychalcones with N-2,2,2-trifluoroethylisatin ketimines catalyzed by a (R)-3,3'-I2-BINOL-boron complex was developed. A broad range of 3,2'-pyrrolidinyl spirooxindole derivatives bearing a CF3-substituted pyrrolidine moiety with four contiguous stereocenters was prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and excellent stereocontrol.

Application of intelligent internet of things and interaction design in Museum Tour.

The rapid development of information technology and the continuous improvement of human spiritual and cultural level have made people's acquisition of knowledge and information increasingly urgent. The information transmission method of traditional navigation systems is single and passive. This study aims to improve user experience and enhance the interactivity of museum visits. This article combines interactive technology in the Internet of Things to conduct in-depth research on the tour guide system in museums. By utilizing IoT technology, optimize the interaction design of the intelligent navigation system, and enhance the convenience and experience of visitors. In the experimental analysis, this article compared the main ticket purchasing methods of tourists, the level of understanding of museum staff about the collection, the amount of information obtained by tourists, and the satisfaction of tourists. The comparison results show that the proportion of electronic ticket purchases has increased by 35 % in terms of ticket purchasing methods. The staff's understanding of the collection has increased by 19 %, the amount of information received by tourists has increased by 12.7 %, and tourist satisfaction has also increased by 24.3 %. The conclusion indicates that the interactive design navigation system based on intelligent Internet of Things and interactive design can effectively meet the needs of different users and provide the public with a richer and deeper cultural experience.

Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2.

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

Development of an environmentally sensitive fluorescent peptide probe for MrgX2 and application in ligand screening of peptide antibiotics.

Mast cells (MCs) are primary effector cells involved in immediate allergic reactions. Mas-related G protein-coupled receptor-X2 (MrgX2), which is highly expressed on MCs, is involved in receptor-mediated drug-induced pseudo-anaphylaxis. Many small-molecule drugs and peptides activate MrgX2, resulting in MC activation and allergic reactions. Although small-molecule drugs can be identified using existing MrgX2 ligand-screening systems, there is still a lack of effective means to screen peptide ligands. In this study, to screen for peptide drugs, the MrgX2 high-affinity endogenous peptide ligand substance P (SP) was used as a recognition group to design a fluorescent peptide probe. Spectroscopic properties and fluorescence imaging of the probe were assessed. The probe was then used to screen for MrgX2 agonists among peptide antibiotics. In addition, the effects of peptide antibiotics on MrgX2 activation were investigated in vivo and in vitro. The environment-sensitive property of the probe was revealed by the dramatic increase in fluorescence intensity after binding to the hydrophobic ligand-binding domain of MrgX2. Based on these characteristics, it can be used for in situ selective visualization of MrgX2 in live cells. The probe was used to screen ten types of peptide antibiotics, and we found that caspofungin and bacitracin could compete with the probe and are hence potential ligands of MrgX2. Pharmacological experiments confirmed this hypothesis; caspofungin and bacitracin activated MCs via MrgX2 in vitro and induced local anaphylaxis in mice. Our research can be expected to provide new ideas for screening MrgX2 peptide ligands and reveal the mechanisms of adverse reactions caused by peptide drugs, thereby laying the foundation for improving their clinical safety.

Highly Enantioselective Chiral Diol-Catalyzed Conjugate Addition of Boronic Acids to α,ß-Unsaturated Trifluoromethyl Ketones.

The (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to α,ß-unsaturated 1,1,1-trifluoromethyl ketones affords corresponding addition products bearing a stereogenic center at the ß-position in moderate to high yields and excellent enantioselectivities (up to 99% ee), without any 1,2-addition product formation. Moreover, this catalytic protocol features mild reaction conditions, a broad substrate scope, suitability for alkenylboronic acids and (hetero)arylboronic acids, and easy scale-up.

Chiral-Boron-Complex Catalyzed Asymmetric Inverse-Electron-Demand Aza-Diels-Alder Reaction of ß-Trifluoromethyl α,ß-Unsaturated Ketones with Cyclic N-Sulfonyl Ketimines.

A highly efficient asymmetric inverse-electron-demand aza-Diels-Alder reaction of ß-trifluoromethyl α,ß-unsaturated ketone with cyclic N-sulfonyl ketimines catalyzed by (R)-3,3'-I2-BINOL-boron-complex was developed. A broad range of fused piperidine derivatives bearing stereogenic carbon containing CF3 motifs were prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and high stereoselectivity.

Enantioselective Synthesis of Chiral Organosilicon Compounds by Organocatalytic Asymmetric Conjugate Addition of Boronic Acids to ß-Silyl-α,ß-Unsaturated Ketones.

Herein, we report (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to ß-silyl-α,ß-unsaturated ketones, furnishing moderate to excellent yields of the corresponding ß-silyl carbonyl compounds with stereogenic centers in excellent enantioselectivities (up to 98% ee). Moreover, the catalytic system features mild reaction conditions, high efficiency, broad substrate scope, and easy scale-up.

5-Hydroxymethylfurfural multimers induce pseudo-allergic reaction through FcεRI at high doses.

Under acidic and high temperature conditions, 5-hydroxymethylfurfural (5-HMF) converted from sugar further produces dimers (Compound II) and trimers (Compound III). The polymers were less reported, and sensitization effect of them was reported in this study. Compounds II and III induced the local and systemic anaphylaxis effect in passive cutaneous anaphylaxis mice model and activated RBL-2H3 cell inducing [Ca2+ ] mobilization, resulting in the release of ß-hexosaminidase and histamine in vitro. The gene knockdown assay figured out that Compounds II and III induced degranulation through FcεRI. Further, Compounds II and III had a certain affinity with FcεRI by cell membrane chromatography and may combine on the "proline sandwich" structure indicated by molecular docking. All above suggested Compounds II and III can induce pseudo-allergic reaction through FcεRI in vivo and in vitro. Our work provides basic research to prove that the newly discovered 5-HMF transformants, Compounds II and III, induce pseudo-allergic reaction in vitro and in vivo through FcεRI, which is different pathway from 5-HMF. In foods with high sugar content, the sensitization of Compounds II and III needs more attention. In high-sugar foods and medicines, especially traditional Chinese medicine injections, the content of transformants needs to be detected.

Convenient Diaryl Ureas as Promising Anti-pseudo-allergic Agents.

Allergic diseases are a group of allergen-induced unfavorable immune responses initiating various symptoms in different organs. Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells has been reported to be responsible for immunoglobulin E (IgE)-independent immune diseases and allergic drug reactions and has therefore been a crucial drug target for the development of anti-pseudo-allergic agents. Considering the active structural features of MRGPRX2, we designed and synthesized a series of diaryl ureas (DPUs). DPUs exert promising potency for inhibiting ß-hexosaminidase release in LAD2 cells with half-maximal inhibitory concentrations (IC50) values of 2.51-0.62 µM, as well as favorable antilocal and systemic anaphylaxis in mice at a dosage of 10 mg/kg. MRGPRX2 is further revealed to participate in the anti-pseudo-allergic activity of DPUs by binding with electrophilic urea and trifluoromethyl substituents. In brief, these results highlight entities with powerful electrophilic substituents as a prospective therapeutic strategy for the treatment of IgE-independent disorders.

Clarithromycin-treated chronic spontaneous urticaria with the negative regulation of FcεRΙ and MRGPRX2 activation via CD300f.

Mast cells (MCs) are main effector cells in chronic spontaneous urticaria (CSU). Both Fc epsilon RI (FcεRΙ)- and MAS-related G coupled receptor-X2 (MRGPRX2)-mediated MC activations affect CSU course. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) has been shown to regulate FcεRΙ activation. However, no study has verified CD300f is a target to cure CSU. Therefore this study aimed to verify whether clarithromycin (CLA) regulates FcεRΙ- and MRGPRX2-mediated MC activations via CD300f and shows therapeutic effect on CSU. The target of CLA was verification. CLA inhibited FcεRΙ- and MRGPRX2-mediated MC activations were shown in vivo and in vitro. A single-center, self-comparison study was performed, and CLA-treated CSU was investigated in 28 patients who were not sensitive to the third-generation antihistamines. Serum inflammatory mediators in patients before and after CLA administration were analyzed. CLA effectively inhibited type Ι anaphylactic reactions and pseudo-allergic reactions in mice. Moreover, CLA inhibited FcεRΙ- and MRGPRX2-mediated MC signaling pathway activation. Regulatory effects of CLA were decreased significantly after CD300f knockdown. CLA effectively alleviated the symptoms of wheal and itch and reduced serum cytokine levels in patients. CLA negatively regulated FcεRΙ- and MRGPRX2-mediated MC activation via CD300f and showed significant therapeutic effect on CSU.

The Effectiveness of Ultrasound-Guided Subacromial-Subdeltoid Bursa Combined With Long Head of the Biceps Tendon Sheath Corticosteroid Injection for Hemiplegic Shoulder Pain: A Randomized Controlled Trial.

Background: Subacromial-subdeltoid (SASD) bursa and long head of the biceps tendon (LHBT) sheath corticosteroid injection are commonly used to treat shoulder pain associated with arthritic shoulder conditions, but effectiveness in the stroke population is unclear. This study aimed to investigate the clinical effectiveness of ultrasound-guided SASD bursa combined with LHBT sheath corticosteroid injection for hemiplegic shoulder pain (HSP) compared with SASD bursa injection alone. Methods: 60 patients with HSP were randomly allocated to the dual-target group (n = 30) and single-target group (n = 30). The single-target group received SASD bursa corticosteroid injection alone, and the dual-target group received SASD bursa and LHBT sheath corticosteroid injection. The primary endpoint was pain intensity measured on a visual analog scale (VAS). The secondary endpoint was passive range of motion (PROM) of the shoulder, Upper Extremity Fugl-Meyer assessment (UEFMA) score, and Modified Barthel Index (MBI) score. PROM and pain intensity VAS were assessed at baseline and weeks 1, 4, and 12 post-treatment. UEFMA and MBI were recorded at baseline and weeks 4 and 12 post-treatment. Results: A total of 141 patients with HSP were screened, and 60 patients were included. Significant differences in the VAS, PROM, UEFMA and MBI were observed at all follow-ups in both groups. The dual-target group showed a significant difference in VAS score compared with the single-target group (3.3 vs. 3.7, p = 0.01) at week 4 and week 12 (2.5 vs. 3.2, p < 0.001). Moreover, the dual-target group showed statistically significant differences in flexion (p < 0.001) at week 12, extension rotation (p < 0.001) at week 12, and abduction at week 1 (p = 0.003) and weeks 4 and 12 (p < 0.001) compared with the single-target group. There were significant differences in FMA and MBI scores in the two groups before and after treatment (p < 0.001), with a more significant increase in the dual-target group compared with the single-target group (p < 0.001) at week 12. Conclusion: The combination of SASD bursa and LHBT sheath corticosteroid injection is superior to SASD bursa injection alone in reducing shoulder pain and improving functional activities in patients with HSP. Clinical Trial Registration: www.chictr.org.cn, Unique identifier: ChiCTR2100047125.

Hotspots and Cutting-Edge Visual Analysis of Digital Museum in China Using Data Mining Technology.

During the last several years, the building and development of digital museums has grown in importance as a study issue of increasing importance. On the other hand, systematic and extensive literature study on digital museums is rare in the academic community throughout the world. This paper employs data mining technology to conduct a comprehensive analysis of the total amount of academic literature, research hotspots, frontiers, and trends in the field of digital museums in China since the beginning of the twenty-first century, including both historical and contemporary data. In this research, the CNIK database and the CiteSpace program are utilized. The findings revealed that the quantity of published literature expanded significantly between 2000 and 2021, with some variations along the way, but that the general growth rate remained consistent. Colleges and universities are the driving force behind academic research in the field of digital museums; research institutes and big museums play a key part in the academic research that is being conducted by digital museums. Cooperation between research institutes, on the other hand, is severely lacking. Furthermore, the advancement of digital technology is an unavoidable byproduct of the efforts to transform the digital museum into a smart museum, as previously said. When it comes to digital museum development in the postepidemic period, the optimization and updating of a user-centered information service platform is the most important step toward long-term success. In order to maintain the richness of Chinese traditional culture while also meeting the expanding cultural requirements of the general public, China's digital museum research has as its ultimate objective the construction of sustainable digital museums that are appropriate for the country's national conditions. The findings also demonstrate that the construction of a Chinese Digital Museum is a study issue with distinct Chinese features that has the potential to contribute to the preservation of Chinese cultural heritage, both tangible and intangible. This research gives insights into the following aspects: researchers and practitioners from across the world will work together to promote a better knowledge of the building and growth of the digital museum in China, among other things.

Synthetic imperatorin derivatives alleviate allergic reactions via mast cells.

Anaphylaxis is a severe systemic allergic reaction that exhibits multiple clinical symptoms. The Mas-related G protein-coupled receptor X2 (MRGPRX2) is recognized as a key cell receptor mediating allergic diseases and drug-induced anaphylactoid reactions. Thus, it has been a promising target for preventing and treating these reactions. Based on the potential activity of imperatorin and active structural feature of MRGPRX2, we first demonstrated that the synthetic imperatorin derivatives (IDs) could significantly inhibit MRGPRX2 agonist-induced degranulation and cytokine release in LAD2 cells, as well as alleviate local and systemic anaphylaxis in mice. The IC50 value of the most promising compound is an order of magnitude lower than that of imperatorin. IDs were further identified to display anti-pseudo-allergic activity by binding MRGPRX2 with the tertiary nitrogen substructures, just liking the reported MRGPRX2-ligand. These results would propose evidence for discovery of agents for treating MCs-dependent allergic disorders.

Dehydroandrographolide targets CD300f and negatively regulated MRGPRX2-induced pseudo-allergic reaction.

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates mast cells (MCs) activation, which is a key target for the treatment of allergic diseases. However, there are few drugs targeting MRGPRX2. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) is a negative regulator of FcεRΙ-mediated MC activation. However, the regulatory effect of CD300f on MRGPRX2 remains unclear. Dehydroandrographolide (DA) is a main contributor of Andrographis paniculata (Burm.f.) Nees (family: Acanthaceae) have been shown to inhibit type I hypersensitivity. The aim of this study was to determine whether DA negatively regulated MRGPRX2-mediated MC activation via CD300f and showed therapeutic effect on pseudo-allergic reactions. Mouse allergic models and MC degranulation were detected in vivo and in vitro, and inflammatory mediators were detected. siRNA interference and Biacore were used to verify the target. DA inhibited pseudo-allergic reactions by reducing vasodilation and serum cytokine levels in mice and inhibited MRGPRX2-mediated MC activation. The regulatory effect of DA was significantly decreased after the knockdown of CD300f expression. Moreover, DA upregulated the phosphorylation level of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2, which are key kinases in the negative regulatory signaling pathways associated with CD300f. In conclusion, DA negatively regulates MRGPRX2-mediated MC activation via CD300f to inhibit pseudo-allergic reactions.

Design and synthesis of first environment-sensitive coumarin fluorescent agonists for MrgX2.

Mas related G-protein-coupled receptor member X2 (MrgX2) has been identified as the crucial receptor in drug induced pseudo-allergic reactions and allergic diseases. In this research, the first type of fluorescent agonists (ZX1, ZX2 and ZX3) for MrgX2 were developed by conjugating environment-sensitive fluorophore coumarin to MrgX2 selective agonists (R)-ZINC-3573. Their environment-sensitive property was confirmed by the dramatically increase of fluorescent intensity after binding to the hydrophobic ligand binding domain MrgX2, which help to overcome the high background signal. Based on these characteristics, they can be used for selective visualization of MrgX2 in living cells even with their own background interference. Among these fluorescent agonists, compound ZX2 possessed splendid spectroscopic properties, outstanding pharmacological activities (EC50 = 0.93 µM, KD = 1.97 µM). And a competitive binding assay was established with ZX2 to analysis the binding affinity of MrgX2 agonists, which shown high coherence with the results of cell membrane chromatography. To our knowledge, these probes are the first fluorescent ligands of MrgX2 with agonistic activity and environment-sensitive property, which is expected to use for the development of MrgX2 molecular pharmacology and serve as a convenient high-throughput screening tool for the drug candidates targeting MrgX2.

Synthesis and evaluation of new potential anti-pseudo-allergic agents.

Pseudo-allergic reactions frequently occur following clinical drug use and sometimes even cause mortal danger. Mas-related G-protein-coupled receptor member X2 (MRGPRX2) is a novel receptor that mediates pseudo-allergy and is an important target in the treatment of allergies. However, to date, there are no synthetic small-molecule inhibitors that prevent anaphylactoid reactions through this pathway. Our preliminary research suggested that B10-S and mubritinib effectively inhibited LAD2 cells. Therefore, two novel derivatives were synthesized by integrating the active substructures of B10-S and mubritinib, according to the molecular docking results. The antiallergic inhibitory effects of the two compounds were preliminarily evaluated in vitro using ß-hexosaminidase release, histamine release, and intracellular Ca2+ mobilization assays, and their binding sites on MRGPRX2 were analyzed by molecular docking. Both substances inhibited ß-hexosaminidase and histamine release in LAD2 cells and decreased intracellular Ca2+ by inhibiting MRGPRX2 in MRGPRX2-HEK293 cells treated with C48/80 in a dose-dependent manner. The docking results suggested that the molecules could competitively bind to the active site on MRGPRX2 and Glu141, which were combined by C48/80. Our study indicated that the two compounds have potential anti-allergic properties, which may provide evidence that will facilitate the development of synthetic molecules with anti-pseudo-allergic activity for clinical use in the future.

Potential relationship between clinical symptoms and the root canal microbiomes of root filled teeth based on the next-generation sequencing.

AIM: To determine the microorganism in root canal systems of root filled teeth with periapical disease and their relationship with clinical symptoms using next-generation sequencing. METHODOLOGY: The roots of 10 extracted teeth were collected from 10 patients who presented with post-treatment apical periodontitis (PTAP; six with symptoms and four without symptoms). Each root was divided horizontally into two parts (apical and coronal segments) and cryo-pulverized. Microbial communities were detected using 16S rDNA hypervariable V3-V4 region. The diversity, principal coordinate analysis and linear discriminant analysis effect size were performed in the symptomatic and asymptomatic groups (apical and coronal parts respectively). A Mann-Whitney test and an analysis of similarities were applied for intergroup analysis, at a significance level of 5%. RESULTS: A total of 23 phyla, 257 genera and 425 species were detected. Firmicutes was the most abundant phylum in all samples. Three phyla (Fusobacteria, Synergistetes and unidentified_Bacteria) and seven genera (Fusobacterium, Porphyromonas, Phocaeicola, Olsenella, Campylobacter, Tannerella and Fretibacterium) were significantly more abundant in the symptomatic patients (p < .05), whereas asymptomatic patients had more Sphingomonas. The species more significantly abundant in the symptomatic samples were Porphyromonas gingivalis, Phocaeicola abscessus, Campylobacter showae, Tannerella forsythia and Olsenella uli (p < .05). CONCLUSIONS: A greater microbial diversity was observed in root filled teeth with PTAP compared to earlier reports. Several genera and species in root canal systems might be associated with clinical symptoms of PTAP.